Using a preclinical model system of Fragile X Syndrome (FXS), the proposed studies will identify new auditory processing based biomarkers that can be used as reliable outcome measures for therapeutics and provide new insights into neural mechanisms underlying auditory hypersensitivity in FXS. FXS is the most common inherited cause of mental impairment, and is a leading genetic cause of autism. Data from humans with FXS and the mouse model (Fmr1 KO) indicate auditory processing deficits. In vivo electrophysiological data from cortical neurons in adult Fmr1 KO mice suggest hyper-excitability in response to sounds and altered spectral and temporal responses. The proposed studies will determine the developmental time course of auditory cortical deficits in Fmr1 knock out (KO) mice, address mechanisms of these deficits and evaluate novel drugs in treating auditory functional deficits. Specific aim 1 will test the hypothesis that auditory processing deficits in the adult Fmr1 KO mice arise due to a deficit in developmental refinement of cortical processing. These studies will also compare auditory cortical responses between mice in which Fmr1 is deleted only in the excitatory neurons to address sources of deficits. In addition, recordings will be obtained from mice in which cortical Fmr1 is deleted only from 3 weeks postnatal to disambiguate developmental versus acute role for Fmr1 in establishing cortical responses in adult mice. Dendritic spine morphology of Al neurons will also be tracked during development to identify possible structural correlates of functional deficits. Specific aim 2 will determine baseline and sound evoked electroencephalogram (EEG) responses in awake, behaving mice. We will determine the effect of candidate drugs in reversing the auditory deficits at the single neuron and EEG/ERP levels. The EEG response will provide high throughput markers to test drugs. These studies will also identify new therapeutic strategies based on analysis of matrix metalloproteases in the auditory cortex in specific aim 3. An integrated approach based on in vivo electrophysiology, neuroanatomy and pharmacology will be used to address mechanisms of auditory processing deficits and drug effects in reversing these deficits.